CB-5339
目录号 : GC20117CB-5339 is a second generation, potent and selective, orally bioavailable, ATP-competitive, small molecule inhibitor of valosin containing protein (VCP)/p97 [1,2].
Cas No.:1863952-15-1
Sample solution is provided at 25 µL, 10mM.
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CB-5339 is a second generation, potent and selective, orally bioavailable, ATP-competitive, small molecule inhibitor of valosin containing protein (VCP)/p97 [1,2]. CB-5339 is an ATP-competitive, small molecule inhibitor of p97 with IC50 of 53 nM [3].
CB-5339 effectively effect on a panel of 16 primary AML patient samples harboring diverse genetic backgrounds. The median IC50 value was 375 nM among these samples [1]. CB-5339 (200 to 1000 nM for 48 hours) induces in vitro loss of viability in AML cell lines (OCI-AML3, MOLM13, SET2 and HEL92.1.7 cells), as well as in fresh, patient-derived (PD) AML cells, including those with TP53 mutations and/or TP53 allelic loss, or with 3q26 (MECOM locus) lesions and EVI1 overexpression [2]. CB-5339 induced accumulation of polyubiquitylated proteins, retention of ERAD substrates, and lethal ER stress in cancer cells mediated by CHOP, DR5 and NOXA [2].
CB-5339 has higher bioavailability than CB-5083 [1]. Treatment with CB-5339 (90 mg/kg) reduced invasion of myeloid leukemia and prolonged survival in an MLL-AF9-driven PDX AML mouse model [1]. In a tail-vein infused, luciferase transduced, aggressive xenograft model of MOLM13 cells, after AML engraftment, co-treatment for 3 weeks with CB-5339 (50 mg/kg/day, PO) and either venetoclax (30 mg/kg/day, PO) or OTX015 (30 mg/kg/day, PO), as compared to treatment with vehicle or each drug alone, significantly reduced the AML burden and improved median and overall survival of the NSG mice, without inducing significant toxicity [2].
References:
[1]. B Roux B, Vaganay C, Vargas J D, et al. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor[J]. Science translational medicine, 2021, 13(587): eabg1168.
[2]. Fiskus W C, Das K, Mill C P, et al. Efficacy of Vcp/p97 Inhibitor, CB-5339, Alone and in Combinations Against High-Risk AML, Including Those with Genetic Lesion in TP53[J]. Blood, 2022, 140(Supplement 1): 8807-8808.
[3]. Wang X, Wen T, Miao H, et al. Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer[J]. Bioorganic & Medicinal Chemistry, 2022, 74: 117050.
| Cell experiment [1]: | |
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Cell lines |
16 primary patient acute myeloid leukemia (AML) cells |
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Preparation Method |
Growth inhibition of 16 primary patient AML samples treated with increasing concentrations of CB-5339 for 6 days. |
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Reaction Conditions |
0-1 µM, 6 days |
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Applications |
The median IC50 value was 375 nM among these samples, thus supporting the translational potential of CB-5339. |
| Animal experiment [2]: | |
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Animal models |
8-week-old male NSG mice, 6-week-old C57BL/6 male mice, or 6-week-old male and female NSGS or NOG-EXL mice |
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Preparation Method |
1x106 MV4-11-luc cells, 100,000 or 200,000 MLLAF9-DsRed-L-GMP cells, or 500,000 patient derived primary AML cells were injected via tail vein into 8-week-old male NSG mice, 6-week-old C57BL/6 male mice, or 6-week-old male and female NSGS or NOG-EXL mice respectively. CB-5339 was delivered through oral gavage at the indicated doses. Doxorubicin and cytarabine were used intraperitoneally, respectively at 0.5 mg/kg for 3 days and 75 mg/kg for 5 days. Mice were imaged at the indicated time points on an IVIS Spectrum to assess bioluminescence. |
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Dosage form |
Oral, CB-5339 at 50 mg/kg for 4 days |
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Applications |
Treatment with CB-5339 reduced invasion of myeloid leukemia and prolonged survival. |
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References: [1]: Roux B, Vaganay C, Vargas J D, et al. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor[J]. Science translational medicine, 2021, 13(587): eabg1168. |
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| Cas No. | 1863952-15-1 | SDF | |
| 化学名 | 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide | ||
| Canonical SMILES | O=C(N)C1=CC=CC2=C1C=C(C)N2C3=NC(NCC4=CC=CC=C4)=C(CCCN5)C5=N3 | ||
| 分子式 | C24H24N6O | 分子量 | 412.49 |
| 溶解度 | DMSO : 41.67 mg/mL | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4243 mL | 12.1215 mL | 24.243 mL |
| 5 mM | 0.4849 mL | 2.4243 mL | 4.8486 mL |
| 10 mM | 0.2424 mL | 1.2122 mL | 2.4243 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet